Regulation and molecular function of the T-box transcription factors Tbx2 and Tbx3 in the development of the murine lung

• Applicant: Professor Dr. Andreas Kispert
• Subject Area: Developmental Biology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264816801

Vertebrate organ development relies on the precise spatiotemporal orchestration of proliferation rates and differentiation patterns in adjacent tissue compartments. During branching morphogenesis of the embryonic lung, a number of signals secreted from the epithelial endodermal branch tips maintain the underlying mesenchyme in an undifferentiated proliferative state which in turn is required to maintain precursor cells in the distal lung bud epithelium, and allow continued outgrowth. Although individual signals that maintain proliferation of precursor tissues have been identified in the development of many organs, including the lung, it has remained unclear how these signals are integrated and translated into cell-cycle control. Our recent work has shown that the T-box transcriptional repressor Tbx2 maintains proliferation and inhibits differentiation of the pulmonary mesenchyme by directly repressing the cell-cycle inhibitor genes Cdkn1a and Cdkn1b. Our additional preliminary work suggests that Tbx2 and the closely related Tbx3 integrate various epithelial signals to repress a diverse set of anti-proliferative gene activities in the mesenchyme. Therefore, we wish to define the upstream regulatory modules and the downstream effectors of Tbx2 and Tbx3 in the developing lunThe specific aims of this proposal are:1. Analysis of the control of Tbx2 andTbx3 expression in the lung mesenchyme.We wish to determine the individual and combined activities of signaling pathways (Shh, Wnt, Bmp and Tgfß) that induce and/or maintain expression of Tbx2/Tbx3 in time and space, and characterize the contribution of Tbx2/Tbx3 function to these signaling activities in the lung.2. Analysis of the molecular function of Tbx2/Tbx3 in the lung mesenchyme. We wish to further characterize the molecular and cellular changes in embryonic lungs lacking Tbx2, Tbx3 and Tbx2/Tbx3, and in adult lungs overexpressing Tbx2, analyze the role of Wnt, Bmp and interferon signaling/interferon regulatory factors as downstream effectors of Tbx2/Tbx, and identify and characterize direct targets of Tbx2 and Tbx3 in this tissue. I expect from these experiments new insight into the regulatory network that maintains branching morphogenesis in the developing lung and into the complexity of the proliferative and differentiation pathways regulated by Tbx2/Tbx3 in the pulmonary mesenchyme. This insight might also be useful to better understand the significance of upregulation of Tbx2 and Tbx3 in a number of cancers.

• DFG Programme: Research Grants